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Process for preparing leukotrienes antagonist

A vinyl and compound technology, applied in the field of preparing 1-cyclopropylacetic acid precursors, can solve the problems of low yield, not particularly suitable for large-scale production, lengthy chromatographic purification and the like

Inactive Publication Date: 2007-07-18
SCHERING AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method is not particularly suitable for large-scale production, as it requires lengthy chromatographic purification of the methyl ester intermediate and / or final product, and its yields are low
Also, the end products as sodium salts are obtained as amorphous solids, which are generally not ideal for pharmaceutical formulations

Method used

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  • Process for preparing leukotrienes antagonist
  • Process for preparing leukotrienes antagonist
  • Process for preparing leukotrienes antagonist

Examples

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preparation example Construction

[0056] Scheme 3 describes an improved process for the preparation of compounds of formula (I) contemplated by the present invention. In step (3a), the dilithium salt of 1-(mercaptomethyl)cyclopropylacetic acid is coupled with the sulfonate of formula (II). Thus, 1-(mercaptomethyl)cyclopropylacetic acid (VIII) is first converted to the dilithium dianion by contacting the former with a lithium base such as n-butyllithium in hexane or heptane and the like conduct. The reaction is carried out in an inert organic solvent such as THF, toluene, or mixtures thereof, at a temperature below 0°C, usually at about -5°C or lower.

[0057] The sulfonate (II) is then added to the solution of the dilithium dianion. The sulfonate can be added directly as a solid or as a solution in an inert organic solvent such as THF or toluene, preferably THF. Due to the limited stability of the sulfonate ester (II) in solution, the sulfonate ester solution is preferably prepared just prior to addition to...

Embodiment 1

[0076] 1,1-Cyclopropyldimethanol Cyclic Sulfite

[0077] Method A:

[0078] To a 1 liter round bottom flask equipped with a stirrer, thermocouple, nitrogen inlet and syringe pump was added dichloromethane (645 ml) and 1,1-cyclopropyldimethanol (10.64 g; 97.93 mmol). The mixture was stirred for 10 minutes to ensure complete dissolution. N,N-Diisopropylethylamine (34.21 ml; 195.86 mmol) was added and the solution was cooled to 0-5°C. Thionyl chloride (7.01 ml; 96.04 mmol) was added subsurface via a Teflon tube via a syringe pump over 60 minutes. The reaction solution was transferred to a separatory funnel containing cold (0-5°C) phosphate buffer (pH=7.2, 650ml). The layers were separated after equilibration. The product solution in dichloromethane was washed with 2wt% sodium chloride solution (650ml), then the product solution was azeotropically dried and concentrated to 50ml at 35-40°C under atmospheric pressure. Yield of title compound determined = 13.07 g (90%)

[0079]...

Embodiment 2

[0083] 1-(Hydroxymethyl)cyclopropylacetonitrile

[0084] Method A:

[0085] A 250 ml round bottom flask equipped with an upper stirrer, thermocouple, distillation head and receiving flask was charged with a solution of the cyclic sulfite of Example 1 in dichloromethane (61 ml; 158.9 mg / ml; 9.69 g ) by distillation at atmospheric pressure to concentrate the solution to approximately 20 ml. Isopropyl acetate (2 x 30ml) was added and distillation continued to a final volume of 13ml. To the solution was added dimethylformamide (21 ml) above 55°C and the solution was cooled to room temperature.

[0086] Into a 250 ml round bottom flask equipped with an upper stirrer, thermocouple, reflux condenser and nitrogen inlet was added 40 ml of cyclic sulfite (9.28 g; 62.6 mmol) in DMF:IPAc (isopropyl acetate) (4: 1) of the above solution. Sodium cyanide (4.61 g; 94 mmol) and sodium iodide (3.75 g; 25.0 mmol) were added at room temperature. The reaction mixture was heated to 70±3°C and ...

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Abstract

The present invention relates to a process for the preparation of a compound of formula (I) or a sodium salt thereofwherein HET is 7-chloroquinolin-2-yl or 6,7-difluoroquinolin-2-yl, which comprises: reacting the dilithium dianion of 1-(mercapto-methyl)cyclopropaneacetic acid with a compound of formula (II)wherein HET is as defined above and L is arylsulfonyl or alkylsulfonyl. The invention further provides the dicyclohexylamine salt of a compound of formula (I).

Description

[0001] cross reference [0002] This application is a continuation-in-part of U.S.S.N. 08 / 174931, filed December 28, 1993, which application is incorporated herein by reference in its entirety. Background of the Invention [0003] Leukotrienes constitute a group of locally acting hormones produced from arachidonic acid in living systems. The main leukotrienes are leukotriene B 4 (abbreviated as LTB 4 ), LTC 4 , LTD 4 and LTE 4 . The biosynthesis of these leukotrienes begins according to the action of 5-lipoxygenase on arachidonic acid to produce known epoxides such as leukotriene A 4 (LTA 4 ), which are converted into other leukotrienes by subsequent enzymatic steps. More detailed biosynthesis and metabolism of leukotrienes can be found in Leukotrienes and Lipoxygenases, ed. J. Rokach, Elsevier, Amsterdam (1989). The role of leukotrienes in living systems and their impact on symptoms of various diseases is also discussed in Rokach's book. [0004] Recently, a number ...

Claims

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Application Information

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IPC IPC(8): C07D215/18A61K31/47A61P11/06C07C215/14C07C313/02C07C323/53C07D215/12C07D215/14
CPCC07C2101/02C07C323/53C07D215/14C07C2601/02A61P11/06A61P29/00A61P37/08
Inventor M·布帕斯J·M·麦南马拉R·P·沃兰蒂D·R·西德勒J·J·伯根
Owner SCHERING AG
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